Abstract
Halopemide is a new psychotropic agent, a structural analogue of the neuroleptics of the butyrophenone type but with different pharmacological and clinical properties. Preliminary clinical findings indicate that halopemide lacks the ability to induce parkinsonism and may be an effective drug in the treatment of psychosis characterized by autism, emotional withdrawal or apathy. Its pharmacological effects at a molecular level in comparison to structurally related neuroleptics and putative metabolites are reviewed.
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Soudijn W, Van Wijngaarden I, Janssen PAJ. US Patent no 4,031,226, 1977.
Rombaut N, Depoorter H, Brugmans J. Halopemide, a new potent non-neuroleptic dopamine-blocker with psychotropic properties. Communication at the XIth CINP Congress, Vienna (Austria), July 9–16, 1978.
Wauters A, Rombaut N. R 34 301 in the treatment of schizophrenia. An open pilot trial in 10 patients. Janssen Clinical Research Report R 34301/3. Beerse: Janssen Pharmaceutica, 1976.
Deberdt R. Anti-autistic properties of halopemide in the treatment of young oligophrenic patients with severe contact disturbances. A double-blind trial in 10 patients. Janssen Clinical Research Report R 34301/1. Beerse: Janssen Pharmaceutica, 1977.
Veltkamp BP. Halopemide in the treatment of infantile autism. A case study. Janssen Clinical Research Report R 34301/4. Beerse: Janssen Pharmaceutica, 1977.
Depoorter H, Martens C, Isebaert L, Glorieux H, Verstraeten L. Therapeutic effect of halopemide. A multicentric open pilot trial in 70 patients. Janssen Clinical Research Report R 34301/5. Beerse: Janssen Pharmaceutica, 1978.
Nolen WA, Jadnanansingh R. Halopemide, a new psychotropic drug. Clinical effects in an open study. Pharmacopsychiatria 1981;14:21–6.
Davis JM. Antipsychotic drugs. In: Kaplan HI, Freedman AM, Sadock BJ, eds. Comprehensive textbook of psychiatry, III. 3rd ed. Baltimore: Williams & Wilkins, 1980:2257–89.
Klein DF, Gittelman R, Quitkin F, Rifkin A. Diagnosis and drug treatment of psychiatric disorders: adults and children. 2nd ed. Baltimore: Williams & Wilkins, 1980.
Hollister LE. Psychiatric disorders. In: Avery GS, ed. Drug Treatment. 2nd ed. Sydney: Adis Press, 1980;1057–121.
Baldessarini RJ. Drugs and the treatment of psychiatric disorders. In: Gilman AG, Goodman LS, Gilman A, eds. Goodman and Gilman's The Pharmacological Basis of Therapeutics. 6th ed. New York: MacMillan Publishing Company, 1980:391–447.
Ayd FJ Jr. Early-onset neuroleptic-induced extrapyramidal reactions: a second survey, 1961–1981. In: Coyle JT, Enna SJ, eds. Neuroleptics: neurochemical, behavioral, and clinical perspectives. New York: Raven Press, 1983:75–92. (Enna SJ, ed. Central Nervous System Pharmacology. Vol. 3).
Baldessarini RJ, Tarsy D. Tardive dyskinesia. In: Lipton MA, DiMascio A, Killam KF, eds. Psychopharmacology: a generation of progress. New York: Raven Press, 1978:993–1004.
Jenner P, Marsden CD. Neuroleptics and tardive dyskinesia. In: Coyle JT, Enna SJ, eds. Neuroleptics: neurochemical, behavioral, and clinical perspectives. New York: Raven Press, 1983:223–53. (Enna SJ, ed. Central Nervous System Pharmacology. Vol. 3).
Sovner R, DiMascio A. Extrapyramidal syndromes and other neurological side effects of psychotropic drugs. In: Lipton MA, DiMascio A, Killam KF, eds. Psychopharmacology: a generation of progress. New York: Raven Press, 1978:1021–32.
Task force on late neurological effects of antipsychotic drugs. Tardive dyskinesia: Summary of a task force report of the American psychiatric association. Am J Psychiat 1980;137:1163–72.
Broekaert A. The neuroendocrine effects of halopemide. Janssen Clinical Research Report R 34301/2. Beerse: Janssen Pharmaceutica, 1977.
Loonen AJM. Halopemide, an antipsychotic agent and R 28935, an antihypertensive agent. Cerebral distribution and receptor interactions. Amsterdam: University of Amsterdam, 1980. 123 pp. Dissertation.
Loonen AJM. Receptorinteractiesin vivo enin vitro. De toetsing van een hypothese en het werkingsmechanisme van halopemide. Pharm Weekbl. 1981;116:1181–7.
Soudijn W. Over neuroleptica. Metabolisme en localisatie (hersenen) van haloperidol en pimozide. Leiden: State University of Leiden, 1969. IIIpp. Dissertation.
Soudijn W, Van Wijngaarden I. Localization of [3H]-pimozide in the rat brain in relation to its anti-amphetamine potency. J Pharm Pharmacol 1972;24:773–80.
Loonen AJM, Van Wijngaarden I, Janssen PAJ, Soudijn W. Regional localization of halopemide, a new psychotropic agent, in the rat brain. Eur J Pharmacol 1978;50:403–8.
Laduron PM, Janssen PFM, Leysen JE. Spiperone: a ligand of choice for neuroleptic receptors. 2. Regional distribution andin vivo displacement of neuroleptic drugs. Biochem Pharmacol 1978;27:317–21.
Naylor RJ, Olley JE. The distribution of haloperidol in rat brain. Br J Pharmacol 1969;36:208P-9P.
Burt DR, Creese I, Snyder SH. Properties of [3H]haloperidol and [3H]dopamine binding associated with dopamine receptors in calf brain membranes. Mol Pharmacol 1976;12:800–12.
Seeman P, Lee T, Chau-Wong M, Tedesco J, Wong K. Dopamine receptors in human and calf brains, using [3H]apomorphine and an antipsychotic drug. Proc Natl Acad Sci USA 1976;734354–8.
Seeman P. Brain dopamine receptors. Pharmacol Rev 1980;32:229–313.
Loonen AJM, Van Wijngaarden I, Janssen PAJ, Soudijn W. Regional distribution of halopemide, a new psychotropic agent, in the rat brain at different time intervals and after chronic administration. Life Sci 1979;24:609–14.
Janssen PAJ, Niemegeers CJE, Schellekens KHL. Is it possible to predict the clinical effects of neuroleptic drugs (major tranquillizers) from animal data? Part I. Neuroleptic activity spectra for rats. Arzneim Forsch 1965;15:104–17.
Janssen PAJ, Niemegeers CJE, Schellekens KHL. Is it possible to predict the clinical effects of neuroleptic drugs (major tranquillizers) from animal data? Part II. Neuroleptic activity spectra for dogs. Arzneim Forsch 1965;15:1196–206.
Janssen PAJ, Niemegeers CJE, Schellekens KHL. Is it possible to predict the clinical effects of neuroleptic drugs (major tranquillizers) from animal data? Part III. The subcutaneous and oral activity in rats and dogs of 56 neuroleptic drugs in the jumping box test. Arzneim Forsch 1966;16:339–46.
Janssen PAJ, Niemegeers CJE, Schellekens KHL, Lennaerts FM. Is it possible to predict the clinical effects of neuroleptic drugs (major tranquillizers) from animal data? Part IV. An improved experimental design for measuring the inhibitory effects of neuroleptic drugs on amphetamineor apomorphine-induced ‘chewing’ and ‘agitation’ in rats. Arzneim Forsch 1967;17:841–54.
Niemegeers CJE. Prediction of side effects. In: Fielding S, Lal H, eds. Neuroleptics. New York: Futura Publishing Company, 1974:98–129. (Fielding S, ed. Industrial Pharmacology. Vol. 1).
Janssen PAJ, Van Bever WFM. Butyrophenones and diphenylbutylamines. In: Usdin E, Forrest IS, eds. Psychotherapeutic drugs. Part II. Applications. New York: Marcel Dekker, 1977:869–921. (Usdin E, ed. Psychopharmacology Series. Vol. 2.)
Niemegeers CJE, Wauquier A, Lenaerts FM. The ‘in vivo’ pharmacology of R 34301 in mice, rats and dogs. Janssen Preclinical Research Report R 34301/2. Beerse: Janssen Pharmaceutica, 1975.
Moore KE, Kelly PH. Biochemical pharmacology of mesolimbic and mesocortical dopaminergic neurons. In: Lipton MA, DiMascio A, Killam KF eds. Psychopharmacology: a generation of progress. New York: Raven Press, 1978:221–34.
Laduron P. Homovanillic acid (HVA) determination in rat brain. Janssen Preclinical Research Report R 34301/5. Beerse: Janssen Pharmaceutica, 1975.
Wauquier A, Van den Broeck WAE. Preliminary study on the effects of halopemide as compared to haloperidol and pimozide on sleep-wake patterns in dogs. Janssen Preclinical Research Report R 34301/13. Beerse: Janssen Pharmaceutica, 1978.
Daniels H, Colpaert FC, Niemegeers CJE. Effects of halopemide (R34301) on maternal behavior in male rats. Janssen Preclinical Research Report R 34301/15. Beerse: Janssen Pharmaceutica, 1979.
Neale R, Fallon S, Gerhardt S, Liebman JM. Acute dyskinesias in monkeys elicited by halopemide, mezilamine and the antidyskinetic drugs, oxiperomide and tiapride. Psychopharmacol [Berlin] 1981;75:254–7.
Smythe GA. The role of serotonin and dopamine in hypothalamic-pituitary function. Clin Endocrinol 1977;7:325–41.
Denef C, Follebouckt JJ. Differential effects of dopamine antagonists on prolactin secretion from cultured rat pituitary cells. Life Sci 1978;23:431–6.
Creese I. Receptor interactions of neuroleptics. In: Coyle JT, Enna SJ, eds. Neuroleptics: neurochemical, behavioral, and clinical perspectives. New York: Raven Press, 1983;183–222. (Enna SJ, ed. Central nervous system pharmacology. Vol. 3.)
Worms P, Broekkamp CLE, Lloyd KG. Behavioral effects of neuroleptics. In: Coyle JT, Enna SJ, eds. Neuroleptics: neurochemical, behavioral, and clinical perspectives. New York: Raven Press, 1983:93–117. (Enna SJ, ed. Central nervous system pharmacology. Vol. 3).
Leysen JE, Gommeren W, Laduron PM. Spiperone: a ligand of choice for neuroleptic receptors. 1. Kinetics and characteristics ofin vitro binding. Biochem Pharmacol 1978;27:307–16.
Ornitz EM, Ritvo ER. The syndrome of autism: a critical review. Am J Psychiatry 1976;133:609–21.
Stahl SM. The human platelet. Arch Gen Psychiatry 1977;34:509–16.
Anonymous. Serotonin, platelets and autism. Br Med J 1978;1:1651–2.
Minderaa RB, Young JG, Cohen DG. Neurochemische aspecten van kinderlijk autisme. Tijdschr Psychiatrie 1983;25:406–21.
Hanley HG, Stahl SM, Freedman DX. Hyperserotonaemia and amine metabolites in autistic and retarded children. Arch Gen Psychiatry 1977;34:521–3.
Leysen JE. Receptors for neuroleptic drugs. Adv Hum Psychopharmacol 1983;4:325–56.
Loonen AJM, Soudijn W. Effects of halopemide, a new psychotropic agent, on the uptake of serotonin by blood platelets. Arch Int Pharmacodyn Ther 1979;237:267–74.
Loonen AJM, Soudijn W. Effects of halopemide on potassium-induced release of radiolabeled neurotransmitters from rat cerebrocortical slicesin vitro. Arch Int Pharmacodyn Ther 1980;247:43–58.
Iversen LL. Biochemical psychopharmacology of GABA. In: Lipton MA, DiMascio A, Killam KF, eds. Psychopharmacology: a generation of progress. New York: Raven Press, 1978:25–38.
Mao CC, Costa E. Biochemical pharmacology of GABA transmission. In: Lipton MA, DiMascio A, Killam KF, eds. Psychopharmacology: a generation of progress. New York: Raven Press, 1978:307–18.
Enna SJ, Bennet JP Jr, Burt DR, Creese I, Snyder SH. Stereospecificity of interaction of neuroleptic drugs with neurotransmitters and correlation with clinical potency. Nature 1976;263:338–41.
Fjalland B. Inhibition by neuroleptics of uptake of3H-GABA into rat brain synaptosomes. Acta Pharmacol Toxicol 1978;42:73–6.
Olsen RW, Ticku MK, Van Ness PC, Greenlee D. Effects of drugs on γ-aminobutyric acid receptors, uptake, release and synthesisin vitro. Brain Res 1978;139:277–94.
Lloyd KG, Drekster S. An analysis of3H-gammaaminobutyric acid (GABA) binding in the human brain. Brain Res 1979;163:77–87.
Dismukes K, Mulder AH. Effects of neuroleptics on release of3H-dopamine from slices of rat corpus striatum. Naunyn Schmiedebergs Arch Pharmacol 1977;297:23–9.
Johnston GAR. Neuropharmacology of amino acid inhibitory transmitters. Ann Rev Pharmacol Toxicol 1978;18:269–9.
Berger PA, Elliott GR, Barchas JD. Neuroregulators and schizophrenia. In: Lipton MA, DiMascio A, Killam KF, eds. Psychopharmacology: a generation of progress. New York: Raven Press, 1978:1071–82.
Enna SJ, Maggi A. Biochemical pharmacology of GABA-ergic agonists. Life Sci 1979;24:1727–38.
Matsui Y, Kamioka T. Potentiation of muscimolinduced hyperactivity by benzodiazepines. J Pharm Pharmacol 1979;31:427–8.
Tanner T. GABA-induced locomotor activity in the rat, after bilateral injection into the ventral tegmental area. Neuropharmacol 1979;18:441–6.
Carlsson A. Mechanism of action of neuroleptic drugs. In: Lipton MA, DiMascio A, Killam KF, eds. Psychopharmacology: a generation of progress. New York: Raven Press, 1978:1057–70.
Melville EM, Turnbull MJ, Wheeler H. Determination ofin vivo activity of putative GABA-like compounds. Br J Pharmacol 1979, 66:123P-4P.
Worms P, Lloyd KG. Influence of GABA-agonists and antagonists on neuroleptic induced catalepsy in rats. Life Sci 1978;23:475–8.
Loonen AJM, Soe-Agnie CJ, Soudijn W. Effects of halopemide on GABA receptor binding, uptake and release. Brain Res 1981;210:485–92.
Mohler H, Okada T. Properties of γ-aminobutyric acid receptor binding with (+)-[3H]-bicuculline methiodide in rat cerebellum. Mol Pharmacol 1978;14:256–65.
Christensen AV, Arnt J, Scheel-Kruger J. Decreased antistereotypic effects of neuroleptics after additional treatment with a benzodiazepine, a GABA agonist or an anticholinergic compound. Life Sci 1979;124:1395–402.
Loonen AJM, Soe-Agnie CJ, Soudijn W. Halopemide and benzodiazepine binding sites. Arch Int Pharmacodyn Ther 1982;258:51–9.
Costa E. The role of gamma-aminobutyric acid in the action of 1,4-benzodiazepines. Trends Pharmacol Sci 1979;1:41–4.
Braestrup C, Nielsen M. Anxiety. Lancet 1982;12:1030–4.
Martin IL. Actions and interactions of GABA. Trends Pharmacol Sci 1983;4:405–6.
Simmonds MA. Multiple GABA receptors and associated regulatory sites. Trends Neurosciences 1983;16:279–81.
Dingemanse J, Breimer DD. Benzodiazepine receptors. Pharmacy International 1984;5:33–6.
Braestrup C, Nielsen M, Honore T. Molecular interactions in the GABA/benzodiazepine receptor, chloride channel complex. High energy radiation inactivation studies. Clin Neuropharmacol 1984;7(suppl 1):562–3.
Karobath M. Interaction of benzodiazepine receptor agonists and inverse agonists with the GABA benzodiazepine receptor complex. Clin Neuropharmacol 1984;7(suppl 1):880–1.
Braestrup C, Squires RF. Pharmacological characterization of benzodiazepine receptors in the brain. Eur J Pharmacol 1978;48:263–70.
Mackerer CR, Kochman RL, Bierschenk BA, Bremner SS. The binding of [3H]diazepam to rat brain homogenates. J Pharmacol Exp Ther 1978;206:405–13.
Haefely W. Molecular aspects of benzodiazepine receptors and their ligands. Clin Neuropharmacol 1984;7 (suppl i):658–9.
Van Rooy HH, Waterman RL, Kraak JC. Dynamic cation-exchange systems for the separation of drugs derived from butyrophenone and diphenylpiperidine by high-performance liquid chromatography and applied in the determination of halopemide in plasma. J Chromatogr (Biomed Appl) 1979;164:177–85.
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Loonen, A.J.M., Soudijn, W. Halopemide, a new psychotropic agent. Pharmaceutisch Weekblad Scientific Edition 7, 1–9 (1985). https://doi.org/10.1007/BF01962862
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DOI: https://doi.org/10.1007/BF01962862